Method for lyophilization using cryogenic refrigeration system

ABSTRACT

A cryogenic refrigeration system for lyophilization is disclosed. The cryogenic refrigeration system includes a cryogenic heat exchanger system adapted for vaporizing a liquid cryogen and using the gaseous cryogen to cool heat transfer fluid and a heat transfer cooling circuit that cools the lyophilization chamber as well as the condenser. The disclosed heat transfer cooling circuit includes a primary recirculation loop adapted for cooling the lyophilization chamber with the heat transfer fluid, a secondary recirculation loop adapted for cooling a condenser with the heat transfer fluid, and one or more valves operatively coupling the cryogenic heat exchanger system, the primary recirculation loop, and the secondary recirculation loop.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 11/897,448 filed Aug. 30, 2007 now U.S. Pat. No. 8,015,841which claims priority to U.S. patent application Ser. No. 60/843,053filed Sep. 8, 2006, the disclosures of which are incorporated byreference herein.

FIELD OF THE INVENTION

The present invention relates to methods of lyophilization usingcryogenic refrigeration systems, and more particularly to a cryogenicrefrigeration system adapted to cool both a lyophilization chamber andthe condenser using a common heat exchanger and heat transfer fluids.

BACKGROUND OF THE INVENTION

Lyophilization or freeze-drying is a sublimation process that removesfree water or other solvent in the form of ice. Freeze-drying isespecially useful in the pharmaceutical, chemical and food industries toremove water or solvent from sensitive synthetic and biological productsbecause it preserves their integrity and activity. The increasing use oflyophilization is driven by the escalating global demand for asepticpackaging, preservation of drugs, and the rise in the production ofbiologics, including protein-based therapeutics and vaccines.

During lyophilization, most of the solvent (e.g. water and/or analcohol) is removed from a product after it is frozen and placed undervacuum. The process actually consists of three separate, butinterdependent steps: freezing; primary drying (ice sublimation); andsecondary drying (moisture desorption). During primary drying, 90% ormore of the solvent changes directly from solid to vapor phase throughsublimation without passing through a liquid phase. The remainingsolvent is adsorbed on the product as moisture. Some of this solvent issubsequently desorbed during the secondary drying process to reach thedesired product stability. As a result of the lyophilization process,the solvent content in the product is reduced to a low level that can nolonger support biological growth or chemical reactions, while stillpreserving the activity and integrity of the freeze-dried product.

Freeze-drying has traditionally been carried out commercially usingmechanical freezing or refrigeration systems. Although mechanicalrefrigeration systems may be used, it is disadvantageous to do sobecause very low temperatures are needed in order to cause the watervapor to freeze out in the condenser of the freeze-dryer. Operatingtemperatures below −50° C. adversely impact the performance, efficiencyand reliability of the mechanical refrigeration systems.

Recent advancements in the field of freeze-drying employ the use ofcryogenic fluids and cryogenic heat exchangers rather than mechanicalrefrigeration systems to carry out the freeze-drying process. The lowoperating temperatures required in a lyophilization process have noadverse impact on cryogenic refrigeration systems driven by liquidnitrogen with a normal boiling point of about −196° C. Cryogenicrefrigeration systems for lyophilization applications are capable ofproviding the rapid and constant cool-down rates throughout the entiretemperature range of interest. Prior art cryogenic cooling systemsrecover the stored cold from liquid nitrogen in specially engineeredcryogenic heat exchangers where the liquid nitrogen and/or gas nitrogenwill cool a heat transfer fluid which in turn cools the lyophilizationchamber. Separately, the cryogenic will cool the condenser by directexpansion in the condenser coils or plates. Unfortunately, the directuse in the condenser of any refrigerant—regardless whether it is atypical hydrocarbon refrigerant or a cryogenic fluid—results intwo-phase flow and uneven heat exchange inside and non-uniform iceformation on the outside of the condenser coils or plates. Also, the useof separate cooling techniques or systems for the lyophilization chamberand the condenser introduces additional complexity of the overallsystem, increases the system footprint and likely adds some additionalcosts to own and operate the system.

What is needed therefore is an advanced cryogenic refrigeration systemthat protects the formulations during lyophilization and that providesincreased flexibility, more uniform cooling and is cost competitive withcomparable mechanical refrigeration systems and overcome thedisadvantages of prior cryogenic refrigeration systems.

SUMMARY OF THE INVENTION

The present invention may be characterized as a method for lyophilizinga product comprising the steps of: (i) placing the product in alyophilization chamber; (ii) cooling a heat transfer fluid in acryogenic heat exchanger to a first temperature; (iii) freezing theproduct in the lyophilization chamber by circulating the cooled heattransfer fluid at the first temperature via a three way control valvedisposed downstream of the heat exchanger system to a primaryrecirculation loop and to the lyophilization chamber and wherein theheat transfer fluid exiting the lyophilization chamber is recycled backto the lyophilization chamber or returned to the cryogenic heatexchanger system; (iv) further cooling the heat transfer fluid in thecryogenic heat exchanger to a second temperature; (v) drying the productin the lyophilization chamber by circulating the cooled heat transferfluid at the second temperature via the three way control valve to asecondary recirculation loop and a condenser or circulating the cooledheat transfer fluid at the second temperature to both the lyophilizationchamber via the primary recirculation loop and the condenser via thesecondary recirculation loop and wherein the heat transfer fluid exitingthe condenser is returned to the cryogenic heat exchanger system; and(vi) selectively diverting a portion of the heat transfer fluid in thesecondary recirculation loop upstream of the condenser to the primaryrecirculation loop upstream of the lyophilization chamber to mix withthe heat transfer fluid in the primary recirculation loop and lower thetemperature of the heat transfer fluid in the primary recirculation loopand the lyophilization chamber.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other aspects, features, and advantages of the presentinvention will be more apparent from the following, more detaileddescription thereof, presented in conjunction with the followingdrawings, wherein:

FIG. 1 is a high level schematic representation of a freeze dryer unitincorporating the present cryogenic refrigeration system; and

FIG. 2 is a more detailed schematic representation of the presentcryogenic refrigeration system and the individual cooling circuits usedin a lyophilization application.

DETAILED DESCRIPTION

With reference to FIG. 1, the illustrated freeze-dryer unit (200) hasvarious main components plus additional auxiliary systems to carry outthe lyophilization cycle. In particular, the freeze-dryer unit (200)includes a lyophilization chamber (202) that contains the shelves (204)and the formulation or product (not shown) to be lyophilized. Theproduct to be lyophilized is specially formulated and typically containsthe active ingredient, a solvent system and several stabilizationagents. Lyophilization of this formulation takes place from specializedcontainers located on hollow shelves. These containers may include vialswith stoppers, ampoules, syringes, or, in the case of bulklyophilization, pans.

The illustrated freeze dryer unit (200) also includes a condenser (206)that is adapted to remove the sublimated and desorbed solvent from thevapor phase by condensing or freezing it out as ice to maintain adequatevacuum inside the freeze-dryer. The condenser (206) can be internallylocated in the lyophilization chamber (202) or as a separate externalunit in communication with the lyophilization chamber (202) through aso-called isolation valve. The freeze dryer unit (200) also preferablyincludes a vacuum pump (208) operatively coupled to the condenser (206)and adapted to pull a vacuum on the lyophilization chamber (202) andcondenser (206).

The cryogenic refrigeration system (210) provides the refrigeration forthe freeze dryer unit (200) by cooling a prescribed heat transfer fluidwhich is circulated to the shelves (204) within the lyophilizationchamber (202) and the condenser (206). As illustrated, the cryogenicrefrigeration system (210) comprises a source of cryogen (208), such asliquid nitrogen, a cryogenic heat exchanger (220), and a heat transferfluid circuit (222), a vent (224), a heater (226) and pumps (227,228).

The cryogenic heat exchanger (220) is preferably an NCOOL™ Non-FreezingCryogenic Heat Exchange System available from Praxair, Inc. An importantaspect of the cryogenic heat exchanger (220) is the vaporization of theliquid nitrogen within or internal to the heat exchanger yet in a mannerthat avoids direct contact of the liquid nitrogen on cooling surfacesexposed to the heat transfer fluid.

The prescribed heat transfer fluid circuit (222) is adapted to circulatea heat transfer fluid and is operatively coupled to both thelyophilization chamber (202) as well as the condenser (206). Morespecifically, the heat transfer fluid circulates inside the hollowshelves (204) within the lyophilization chamber (202) to preciselycommunicate the cooling or heating through the shelves (204) to theproduct as needed. In addition the prescribed heat transfer fluid alsoflows through the condenser (206) to provide the cooling means necessaryto condense out the solvent vapors originating from the sublimating iceand desorbing solvent.

Pump (227) and heater (226) are disposed along the heat transfer fluidcircuit (222) upstream of the lyophilization chamber (202) anddownstream of the cryogenic heat exchanger (220). The pump (227) issized to move the heat transfer fluid through the heat transfer circuit(222) at the required flow rates. The heater (226) is preferably anelectric heater adapted to provide supplemental heat to the heattransfer fluid and the lyophilization chamber (202) as may be requiredduring the drying processes.

As seen in the embodiment represented in FIG. 1, the condenser (206) isalso cooled by a recirculating low temperature heat transfer fluid.Refrigeration of the heat transfer fluid flowing through the condenser(206) is also provided by a cryogenic heat exchanger (220). Thecryogenic heat exchanger (220) is capable of cooling heat transfer fluidcontinuously without freezing. During the drying phases, the cryogenicheat exchanger (220) is set or adapted to achieve the lowest temperaturerequired for the condenser (206). As described above, the cryogenic heatexchanger (220) pre-evaporates liquid nitrogen into a cryogenic cold gasfor heat transfer to the heat transfer fluid. Through pre-evaporation ofthe liquid nitrogen assures the liquid nitrogen avoids boiling offdirectly over a heat exchange surface where the heat transfer fluid isdisposed on the other side. Such arrangement avoids freezing of thecryogenic heat exchanger (220) since liquid nitrogen boils at about −196degrees Centigrade at atmospheric pressure.

Although not shown, the freeze-dryer unit (200) also includes variouscontrol hardware and software systems adapted to command and coordinatethe various parts of the freeze-drying equipment, and carry out thepre-programmed lyophilization cycle. The various control hardware andsoftware systems may also provide documentation, data logging, alarms,and system security capabilities as well.

In addition, auxiliary systems to the freeze-dryer unit (200) mayinclude various subsystems to clean and sterilize the lyophilizationchamber (202), auto-load and unload the product in the lyophilizationchamber (202); and associated cryogenic system accessories such asrefrigeration skids, liquid nitrogen tanks, phase separating system,piping, valves, sensors, etc.

An important feature of the illustrated embodiment is the utilization ofa single indirect non-freezing cryogenic heat exchange system (210) toprovide refrigeration to the freezing chamber and the condensersimultaneously at different temperatures as needed. In typicalfreeze-drying applications the lyophilization chamber (202) requires alarge refrigeration demand (i.e. large drop in temperature to freeze theproduct within the lyophilization chamber representing a load with largeheat capacity and significant latent heat of fusion) for a relativelyshort period of time while the condenser (206) typically requires alower refrigeration demand but for a significantly longer duration orcooling time.

It is also important in lyophilization applications that the temperatureof the frozen product in the lyophilization chamber (202) be preciselycontrolled and often kept steady without any adverse temperature spikesor variations within the lyophilization chamber (202) including, forexample, temperature variations within the lyophilization chamber ofgreater than about 1 or 2 degrees Centigrade.

Turning now to FIG. 2, there is shown another schematic representationof the preferred cryogenic refrigeration system (2) applied to orintegrated within a freeze-dryer unit. In a broad sense the cryogenicrefrigeration system (2) includes a cryogenic cooling circuit (100) anda flexible cooling circuit (102). In the illustrated embodiment, theheat transfer fluid flowing within the flexible cooling circuit (102) iscontrollably switched in and out of a primary recirculating loop (104)and a secondary recirculating loop (106) to effectively and efficientlysatisfy the refrigeration loads and temperature requirements associatedwith both the condenser (115) and the lyophilization chamber (110).

The cryogenic cooling circuit includes a source of liquid nitrogen (notshown), a cryogenic heat exchanger (105), and an exhaust or vent line(108). Liquid nitrogen (5) at cryogenic temperatures is supplied to thecryogenic heat exchanger (105). Within the cryogenic heat exchanger(105), the liquid nitrogen (5) is vaporized into a cryogenic coldnitrogen gas (7). The cryogenic cold nitrogen gas (7) is redirectedwithin the heat exchanger (105) to cool the incoming heat transferfluid. After transferring most of its refrigeration capacity to the heattransfer fluid in the cryogenic heat exchanger (105), the residualnitrogen gas (8) is exhausted from the heat exchanger (105) via a ventline (108). In some applications, it may be possible to utilize thevented nitrogen gas in some other cooling application or industrial gasapplication within the facility. The structure and operation of thepreferred cryogenic heat exchanger (105) is described in detail in U.S.Pat. No. 5,937,656 (Cheng et al.) the disclosure of which isincorporated by reference herein.

The heat transfer fluid flowing within the flexible cooling circuit(102) enters the cryogenic heat exchanger (105) via conduit (10), iscooled down by the vaporized cold nitrogen gas (7), and exits thecryogenic heat exchanger (105) via conduit (12) as a cold heat transferfluid. The cold heat transfer fluid is circulated to the lyophilizationchamber (110) via a primary recirculation loop (104) including aplurality of conduits (15, 23, 24, 26, and 38) and to the condenser(115) via a secondary recirculation loop (106) including a plurality ofconduits (16, 18, and 19).

An important aspect of the illustrated embodiment is the flexiblecooling circuit (102) that includes two recirculating loops (104,106)fed from the cryogenic heat exchanger (105) and fluidically coupledtogether by one or more cross-over valves (70, 80) and a diversioncontrol valve (85). In this manner, the lyophilization chamber (110) maybe cooled at the full refrigeration capacity (i.e. maximum cool-downrate) provided by the cryogenic heat exchanger (105) by directingsubstantially all or a significant portion of the cold heat transferfluid exiting the cryogenic heat exchanger (105) directly to thelyophilization chamber (110) via the primary recirculation loop (104).Once the freezing of the product in the lyophilization chamber (110) iscomplete, the refrigeration demand for the lyophilization chamber (110)is reduced and the cold heat transfer fluid from the cryogenic heatexchanger (105) is redirected to the secondary recirculation loop (106)to meet the refrigeration demands of the condenser (115) during theprimary and secondary drying phases of the lyophilization process.

Also, after the initial freezing phase and during the primary andsecondary drying phases, the primary recirculation loop (104) is adaptedto recirculate the heat transfer fluid through the lyophilizationchamber (110) while restricting the return of the heat transfer fluid tothe cryogenic heat exchanger (105). Thus, the primary recirculation loop(104) becomes a partially closed refrigeration loop adapted to keep thelyophilization chamber at the desired temperature.

Referring again to FIG. 2, during the primary and secondary dryingphases the three-way valve (70) preferably redirects the cold heattransfer fluid from conduit (12) to the secondary recirculation loop andhas completely stopped feeding the cold heat transfer fluid to the pump(120) of the primary recirculation loop (104). A second three-way valve(80) disposed in the primary recirculation loop (104) is also activatedduring the drying phases to redirect the heat transfer fluid in theprimary recirculation loop (104) such that it no longer feeds thecryogenic heat exchanger (105). In this manner, an isolation circuit(136) is formed including conduits (23, 24, 25, and 26) with the heattransfer fluid exiting the lyophilization chamber (110) recirculatingvia conduits (25,26) back to the pump (120) and again to thelyophilization chamber (110) via conduits (23, 24) and heater (125). Towarm up the chamber (110) in a very slow and precise rate, a smallamount of cold heat transfer fluid is bled from the secondary circuit(106) through the diversion control valve (85). This avoids over heatingin the chamber (110) shelves for slow drying formulations.

As indicated above, the condenser (115) is cooled to the desiredtemperature by controlling the temperature and flow of heat transferfluid in the secondary recirculating loop (106). During the primary andsecondary drying phases, the flow of heat transfer fluid in thesecondary recirculating loop (106) is generally fed from a stream ofheat transfer fluid via conduit (12) directly from the cryogenic heatexchanger which is preferably at a desired temperature set point.However, a portion of the cold heat transfer fluid may be diverted viaconduit (17) from the secondary recirculation loop (106) to the primaryrecirculation loop (104) to keep the primary recirculation loop (104) atthe desired temperature when additional cooling is needed. In addition,a heater (125) is also used in the primary recirculation loop (104) andisolation circuit (136) to raise the temperature of the heat transferfluid within the isolation circuit (136) and lyophilization chamber(110) when additional heating is needed. Such heating and coolingadjustments are preferably made at very slow, precise and controlledrates in order to maintain the temperatures of the shelves, vials andits contents at the desirable value.

Diversion of the cold heat transfer fluid from the secondaryrecirculation loop (106) to the primary recirculation loop (104) ispreferably achieved using a diversion control valve (85) and a pump(120) operatively associated with the primary recirculation loop (104).The illustrated embodiment of FIG. 2 depicts a diversion loop (17)disposed between the primary recirculation loop (104) and the secondaryrecirculation loop (106). The diverted cold heat transfer fluid from thesecondary recirculation loop (106) mixes with the warmer heat transferfluid in the primary recirculation loop (104) that is isolated andrecirculating through the lyophilization chamber (110).

Bleeding or diverting a small amount of heat transfer fluid from thesecondary recirculation loop (106) to the primary recirculation loop(104) cannot occur if the primary recirculation loop (104) is fullyclosed and the line pressure in the secondary recirculation loop and inconduit (16) is lower or equal to the line pressure in the primaryrecirculation loop (104) and conduit (25). To make that transferpossible, pump (130) in the secondary recirculation loop (106) shouldhave a higher flow capacity and pressure head than pump (120) in theprimary recirculation loop (104). As the diverted cold heat transferfluid flows into the primary recirculation loop (104), overpressurization may occurs. In such case, the excess flow is released byrelief valve (90) into an overflow circuit (140) including a pluralityof conduits (36, 43, 28, 45, and 48), valves (90, 95) and buffer tank(50).

The heat transfer fluid within the primary recirculation loop (104) willtypically expand and contract during the drying phases as a result ofthe temperature swings caused by the continuous heating and cooling ofthe heat transfer fluid therein. To avoid cavitating the pumps, it isimportant that no gas bubbles be present in the recirculating loops fromthe heat transfer fluid expansion and contraction. To address thisoperating concern, the expanding heat transfer fluid is released fromthe primary recirculation loop via relief valve (90) as needed.Similarly, during the cooling temperature swings, the heat transferfluid in the primary recirculation loop (104) will contract and a checkvalve (95) will open to allow backfill of the excess heat transfer fluidback into the primary recirculation loop (104). A buffer tank (50) isoperatively disposed in the overflow circuit (140) to allow for thevariations in volume due to the thermal expansion and contraction of theheat transfer fluid.

Operation of the embodiment illustrated in FIG. 2 is best understoodfrom consideration of the following description. In a typicallyophilization process, the first operation is the freezing step wherethe shelves of the lyophilization chamber (110) are cooled down to aprescribed temperature. To facilitate the rapid cool-down of thelyophilization chamber (110), the cryogenic heat exchanger (105) is setto the desired lyophilization chamber temperature (e.g., −50 degreeCentigrade). During this operation, a three-way valve (70) blocks thecold heat transfer fluid from going to the condenser (115) and divertssubstantially all the fluid toward the lyophilization chamber (110) viaconduit (15). A recirculating pump (120) moves this heat transfer fluidthrough the primary recirculation loop (104). In a typical application,the cold heat transfer fluid flowing through the primary recirculationloop (104) will reduce the temperature on the shelves to the desiredtemperature within 1 to 2 hours or less.

During this maximum cool-down rate phase or freezing phase, the heattransfer fluid exiting the lyophilization chamber (110) via conduit (26)may be a few degrees warmer than the heat transfer fluid in conduit (24)at the inlet of the lyophilization chamber (110). The warmer heattransfer fluid returns to the cryogenic heat exchanger (105) via athree-way transfer valve (80) adapted to controllably couple the heatexchanger with the primary recirculation loop (104). The warmer heattransfer fluid exits from the three-way valve (80) via conduit (38) andconnects to the inlet line (10) of the cryogenic heat exchanger to forma complete heat transfer circuit for the lyophilization chamber (110).

During this freezing phase, the cryogenic refrigeration system (2) holdsthe temperature of the lyophilization chamber (110) at the prescribedset point for several hours to ensure the products inside the vials orpans placed on the shelves are frozen completely. The exact temperatureprofile during this freezing phase may vary depending on the product tobe frozen. For example, some lyophilization processes require steep rampdown to the prescribed temperature, whereas other lyophilizationprocesses require initial cool-down followed by a plateau or a latetemperature rise in the lyophilization chamber to anneal the ice crystalstructure in the product.

After the vials in the lyophilization chamber (110) have been properlychilled and the products are frozen, the second step is to chill thecondenser (115) to start the primary and secondary drying processes. Thecondenser (115) must be cold enough to freeze and capture the water (orsolvent) vapor leaving from the lyophilization chamber (110) via flowpath (60) during the sublimation step. This is accomplished by changingthe set point of the cryogenic heat exchanger (105) to be 10 to 20degrees Centigrade colder than the lyophilization chamber temperature orabout, −60 or −70 degrees Centigrade.

The three-way valve (70) is again activated to redirect the flow (15)from the cryogenic heat exchanger (105) to the condenser (115) via thesecondary recirculation loop (106). The colder heat transfer fluid (e.g.at −60 degrees Centigrade) enters the condenser (115) and drops down thetemperature of the condenser (115) at a prescribed rate. The warmer heattransfer fluid exiting the condenser (115) via conduit (18) may be a fewdegrees warmer than the temperature of the heat transfer fluid enteringthe condenser (115) via conduit (16). The warmer heat transfer fluid isthen transferred back to the cryogenic heat exchanger (105) using arecirculating pump (130). The warmer heat transfer fluid exiting thepump (130) via conduit (19) returns to the cryogenic heat exchanger(105) through inlet line (10).

However, because the lyophilization chamber (110) needs to maintain amaximum uniform temperature at the shelves (e.g., −50 degreesCentigrade), a continuous flow of heat transfer fluid must be maintainedin the isolated primary recirculation loop (104). Preferably, thetemperature of the lyophilization chamber (110) should rise under atight temperature control of not more than about 0.5-2.0 degreesCentigrade per hour. Temperature control of the lyophilization chamber(110) during this phase is preferably accomplished by bleeding in asmall amount of the colder heat transfer fluid from the secondaryrecirculation loop (106) through diversion control valve (85) anddiversion loop (17) where additional cooling of the heat transfer fluidis needed and/or heating the fluid within the primary recirculation loopwith an electric heater (125) where additional heating of the heattransfer fluid is desired.

When the condenser (115) is fully cooled to its final temperature,vacuum is created by a vacuum pump (33) for both the condenser (115) andthe lyophilization chamber (110). The ice in the frozen vials is beingsublimated into water or solvent vapor under vacuum conditions andenters the colder condenser via flow path (60). The extracted water orsolvent vapor is refrozen and condensed on the condenser surface as ice,and any non-condensable matter is passed to the vent. The condensertemperature setting is adjusted as needed to maintain the desired vacuumlevel in the lyophilization chamber.

While the present invention has been described with reference to apreferred embodiment, as will occur to those skilled in the art,numerous changes, additions and omissions may be made without departingfrom the spirit and scope of the present invention, as defined by theappended claims.

What is claimed is:
 1. A method for lyophilizing a product comprisingthe steps of: placing the product in a lyophilization chamber;vaporizing a liquid cryogen and cooling a heat transfer fluid in acryogenic heat exchanger to a first temperature using the gaseouscryogen; freezing the product in the lyophilization chamber bycirculating the cooled heat transfer fluid at the first temperature viaa three way control valve disposed downstream of the cryogenic heatexchanger to a primary recirculation loop configured to cool thelyophilization chamber and wherein the heat transfer fluid exiting thelyophilization chamber is recycled back to the lyophilization chamber orreturned to the cryogenic heat exchanger; further cooling the heattransfer fluid in the cryogenic heat exchanger to a second temperature;drying the product in the lyophilization chamber by circulating thefurther cooled heat transfer fluid at the second temperature via thethree way control valve to a secondary recirculation loop configured tocool a condenser or circulating the further cooled heat transfer fluidat the second temperature to both the lyophilization chamber via theprimary recirculation loop and the condenser via the secondaryrecirculation loop and wherein the heat transfer fluid exiting thecondenser is returned to the cryogenic heat exchanger; and selectivelydiverting a portion of the heat transfer fluid in the secondaryrecirculation loop via a diversion valve from a location downstream ofthe three way control valve and upstream of the condenser to the primaryrecirculation loop at a location downstream of the three way controlvalve and upstream of the lyophilization chamber to mix with the heattransfer fluid in the primary recirculation loop and lower thetemperature of the heat transfer fluid in the primary recirculation loopand the lyophilization chamber.
 2. The method of claim 1 wherein thetemperature of the heat transfer fluid within the primary recirculationloop and the temperature of the lyophilization chamber are preciselycontrolled during the drying step by selectively: (i) heating the heattransfer fluid within the primary recirculation loop using a heaterdisposed in the primary recirculating loop to raise the temperature ofthe heat transfer fluid in the primary recirculation loop; and/or (ii)diverting a portion of the heat transfer fluid in the secondaryrecirculation loop to mix with the heat transfer fluid in the primaryrecirculation loop and lower the temperature of the heat transfer fluidin the primary recirculation loop and the lyophilization chamber.
 3. Themethod of claim 1 wherein the heat transfer fluid exiting thelyophilization chamber is recycled back to the lyophilization chamberduring the drying step without passing to the cryogenic heat exchanger.4. The method of claim 1 wherein the heat transfer fluid exiting thelyophilization chamber is returned to the cryogenic heat exchangerduring the freezing step.
 5. The method of claim 1 wherein a portion ofthe heat transfer fluid in the primary recirculation loop is directed toan expansion circuit during volumetric expansion of the heat transferfluid in the primary recirculation loop and heat transfer fluid from theexpansion circuit is directed to the primary recirculation loop duringvolumetric contraction of the heat transfer fluid in the primaryrecirculation loop.